Allogeneic hematopoietic stem cell transplant (HCT) has the potential to cure patients with leukemia, lymphoma, and other hematologic malignancies; however, it is limited by significant treatment-related morbidity, and mortality ranges from 20-30%. The main cause of treatment-related mortality is graft versus host disease (GVHD), in which the transplanted donor immune cells (graft) attack patient tissues (host). GVHD affects approximately half of HCT patients despite the use of standard prophylactic drugs. There is an urgent need for new prophylactic agents targeting novel pathways. While traditional prophylactic agents focus on T cells, emerging evidence suggests an important role for the innate immune system. Neutrophil elastase (NE) drives local and systemic inflammation by cleaving and releasing proteoglycans such as heparan sulfate (HS). Our group has shown that HS stimulates alloreactive T- cell responses, leading to inflammation and GVHD. Given the role of NE and HS in the pathogenesis of GVHD, a NE inhibitor may successfully block this pathway before development of GVHD. AZD9668 is a potent, selective, and reversible inhibitor of NE that is being studied for treatment of pulmonary chronic GVHD (ClinicalTrials.gov NCT02669251, PI: Pavletic (proposal co-PI)). Given its low toxicity profile in 12 completed clinical trials with over 1000 patients studied, AZD9668 may be a safe and effective prophylactic strategy to inhibit NE, reduce heparan sulfate, prevent GVHD, and improve survival. UG3: Our goal is to use our murine HCT model to test the hypothesis that AZD9668 prevents GVHD. Positive results would support progression to phase 1c and 2 clinical trials. As part of this preclinical trial, we will determine the role of HS, desmosine (an elastin degradation product) and other potential biomarkers of NE activity and GVHD to support future clinical trials UH3: The first goal is to determine the optimal dose and safety of AZD9668 in a phase 1c trial of HCT patients. Our second goal is to test the hypothesis that AZD9668 reduces GVHD in a randomized, double blind, placebo-controlled phase 2 trial. In addition to evaluating efficacy and safety, we will also evaluate biomarkers of target modulation and GVHD. Our group has a strong track record of milestone-driven science, spanning the gamut from lab discovery to product development to clinical trials, and experience with INDs and industry collaborations culminating in the successful completion of projects. We have expertise with the murine models described in the UG3, including NE inhibition to decrease heparan sulfate and prevent GVHD, as well as clinical trial experience with GVHD prophylaxis and treatment , including with the study drug. We are perfectly positioned to partner with AstraZeneca to test a new therapeutic use AZD9668 for GVHD prophylaxis.